US10605751B2 - System and method for determining a quantity of magnetic particles - Google Patents

System and method for determining a quantity of magnetic particles Download PDF

Info

Publication number
US10605751B2
US10605751B2 US15/549,466 US201615549466A US10605751B2 US 10605751 B2 US10605751 B2 US 10605751B2 US 201615549466 A US201615549466 A US 201615549466A US 10605751 B2 US10605751 B2 US 10605751B2
Authority
US
United States
Prior art keywords
frequency
magnetic field
determining
volume
magnetic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active, expires
Application number
US15/549,466
Other languages
English (en)
Other versions
US20180031500A1 (en
Inventor
Joeri VERBIEST
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
PEPRIC NV
Original Assignee
PEPRIC NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by PEPRIC NV filed Critical PEPRIC NV
Assigned to PEPRIC NV reassignment PEPRIC NV ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: VERBIEST, Joeri
Publication of US20180031500A1 publication Critical patent/US20180031500A1/en
Application granted granted Critical
Publication of US10605751B2 publication Critical patent/US10605751B2/en
Active legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N24/00—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects
    • G01N24/10—Investigating or analyzing materials by the use of nuclear magnetic resonance, electron paramagnetic resonance or other spin effects by using electron paramagnetic resonance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/28—Details of apparatus provided for in groups G01R33/44 - G01R33/64
    • G01R33/281—Means for the use of in vitro contrast agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/60—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using electron paramagnetic resonance

Definitions

  • the invention relates in general to the field of characterization of magnetic particles, e.g. paramagnetic particles. More in particular, the invention relates to a system and a method for determining a quantity of magnetic particles present in a volume, as well as to imaging methods based thereon.
  • Electron paramagnetic resonance allows spectroscopic analysis of substances based on physical concepts analogous to those used in nuclear magnetic resonance (NMR). While NMR allows analysis of substances containing nuclides with non-zero spin, EPR is only applicable to substances containing chemical agents that possess at least one unpaired electron. NMR proves particularly useful in the analysis of substances comprising hydrogen atoms, which are abundantly present in water and hydrocarbons. Furthermore, Magnetic Resonance Imaging (MRI), an imaging technique based on NMR, is a valuable tool in medical diagnosis, due to the subtle contrasts caused by water density and complex spin-spin and spin-lattice interactions in different tissues.
  • MRI Magnetic Resonance Imaging
  • EPR has found less application in the past because all electrons in most stable chemical compounds are paired.
  • the strength of EPR lies in its high specificity.
  • EPR can readily be used for detection and imaging of free radicals in tissues, but the development of specific spin-labeled biological tracer molecules has spawned opportunities for the usage of EPR, and particularly the usage of EPR-based imaging techniques, for analysis of diverse physiological functions in biology and medicine. This opens the way for new tracers, specific to biological mechanisms that can't be studied by conventional means, and for alternatives to tracers used in nuclear medicine, without the implied radiation exposure caused by radionuclides.
  • EPR typically uses DC magnetic fields of 5 mT to 1.25 T or higher to cause magnetic polarization of particles with non-zero electron spin. Narrow-band radio-frequent waves are used to disturb the magnetization and cause resonance.
  • the frequency at which resonance occurs referred to as the Larmor precession frequency, is dependent on the applied magnetic field strength and specific material properties, and can range from 200 MHz for low field strengths to 35 GHz or higher for strong fields.
  • the low-field ( ⁇ 30 mT) low-frequency ( ⁇ 1 GHz) region is particularly of interest for applications in biology and medicine because of diminished dielectric loss in tissues.
  • Quantification of the amount of magnetic, e.g. paramagnetic, particles using EPR signals can be performed directly on the EPR signal obtained using conventional EPR measurements. Nevertheless, in order to deal with a wide range of concentrations and to perform accurate quantification, there is still room for improvement.
  • EPR electron paramagnetic resonance
  • the present invention relates to a method of determining a quantity of magnetic particles, e.g. paramagnetic particles, enclosed in a volume, the method comprising the steps of:
  • the modulation of the resultant magnetization may be an amplitude modulation by the time-varying field, but also may be any another type of modulation by the time-varying field.
  • the “quantity” can be expressed as a number of atoms, number of cells, or as a mass or as a concentration (in said volume), or in other ways.
  • the mass that can be detected is at least in the range of 9 ng to 4500 ⁇ g in a volume of for example about 30 to about 150 ⁇ l.
  • the magnetic particles may for example be Fe2O3 or Fe3O4, for which the electron paramagnetic behavior is known to the person skilled in the art. Such types of particles also are widely applicable, e.g. in characterization experiments as well as in medical applications. It is an advantage of embodiments of the present invention in that it allows the quantity to be accurately determined, irrespective of the size or shape of the particles, (e.g. nanoparticles having an average diameter ranging from 20 nm to 500 nm).
  • the paramagnetic particle is iron related
  • the first frequency is about 200 Hz
  • the magnitude of the first magnetic field is about 10.7 mT peak
  • the second frequency is about 300 MHz.
  • the frequencies f B1 +nf B0 is also known as the “upper-side-band”, the frequencies f B1 ⁇ nf B0 is also known as the “lower side-band”. These frequencies correspond to the first upper side-band and to the first lower side-band of the modulated waveform.
  • Determining from said power and/or voltage a quantity of the magnetic particles, e.g. paramagnetic particles enclosed in the volume may comprise determining a quantity based on a linear relationship between the power and/or voltage of said at least one spectral component and the mass of said magnetic particles, e.g. paramagnetic particles.
  • Determining from said power and/or voltage a quantity of the magnetic particles, e.g. paramagnetic particles, enclosed in the volume may comprise comparing said power and/or voltage with a reference power determined for a known quantity of said magnetic particles, e.g. paramagnetic particles.
  • the reference value is typically a value obtained by calibration using a sample volume with a known quantity of said element. Such a calibration may be performed at the time of measurement of the unknown sample but also may be a stored calibration measurement of which the result can be re-used for a plurality of further measurements.
  • the time varying first magnetic field may be a periodic time varying field.
  • the time varying first magnetic field may have a sinusoidal waveform.
  • the time varying second magnetic field may be a periodic time varying field.
  • the time varying second magnetic field may have a sinusoidal waveform.
  • the frequency of the first magnetic field, B 0 can be almost DC to frequencies up to a several kHz.
  • the frequency of the first magnetic field can be a frequency in the range of 10 Hz to 30000 Hz, preferably in the range of 70 Hz to 400 Hz, for example about 200 Hz.
  • the frequency of the second magnetic field, B 1 can be almost few MHz to frequencies up to a several MHz.
  • the frequency of the second magnetic field can be a frequency preferably in the range of 50 MHz to 1000 MHz, for example about 300 MHz.
  • the requirement for building a measurement equipment is that the system itself, without the SUT (Sample Under Test) is an linear time invariant system.
  • the SUT itself can be non-linear.
  • the present invention also relates to a system for determining a quantity of magnetic particles, e.g. paramagnetic particles, enclosed in a volume, the system comprising:
  • the system furthermore may comprise a memory for storing a reference power and/or voltage determined for a known quantity of said magnetic particles, e.g. paramagnetic particles and the processor being programmed for comparing the determined power and/or voltage with the reference power and/or voltage for determining a quantity of the magnetic particles, e.g. paramagnetic particles, enclosed in the volume.
  • a memory for storing a reference power and/or voltage determined for a known quantity of said magnetic particles, e.g. paramagnetic particles and the processor being programmed for comparing the determined power and/or voltage with the reference power and/or voltage for determining a quantity of the magnetic particles, e.g. paramagnetic particles, enclosed in the volume.
  • the processor may comprise a means for calculating a frequency spectrum of the resultant magnetization.
  • the means for calculating a frequency spectrum may comprise a means for performing a (discrete) Fourier-transform, by using for example the Fast Fourier Transform or the Goertzel algorithm.
  • the processor may be part of a specific processing unit integrated in the system or may be a separate processing unit not integrated in the measurement system.
  • the present invention also relates to a method of imaging an object, the method comprising applying a method of determining a quantity of magnetic particles, e.g. paramagnetic particles, in a given volume as described above at a plurality of positions in the object, the determining being applied after administration of a dilution comprising said magnetic element, paramagnetic element to an object.
  • a method of imaging an object comprising applying a method of determining a quantity of magnetic particles, e.g. paramagnetic particles, in a given volume as described above at a plurality of positions in the object, the determining being applied after administration of a dilution comprising said magnetic element, paramagnetic element to an object.
  • FIG. 1 is a flowchart illustrating an embodiment of a method according to the present invention.
  • FIG. 2 is a schematic block-diagram of a system according to the present invention.
  • FIG. 3 shows a schematic representation of the behavior of superparamagnetic particles in a magnetic field as can be described by Langevin theory and electro-paramagnetic resonance effects, as can be used in embodiments of the present invention.
  • FIG. 4 illustrates the phenomenon of “precession”, as used in embodiments according to the present invention.
  • FIG. 5 shows an example of a typical setup as can be used in an embodiment of the present invention.
  • FIG. 6 shows a frequency spectrum (measured with a spectrum analyzer having a heterodyne receiver front end), as can be obtained using a method according to an embodiment of the present invention.
  • FIG. 7 shows an example of a frequency spectrum (measured with a spectrum analyzer having a heterodyne receiver front end) the spectrum being a spectrum of the measured signal, for a volume containing a “Rienso® dilution A, i.e. Rie A” sample containing 4500 ⁇ g (microgram) Fe, illustrating an embodiment of the present invention.
  • FIG. 8 shows an example of a frequency spectrum (measured with a spectrum analyzer, which has typ. a heterodyne receiver front end) of the measured signal, for a volume containing a “Rienso® dilution L, i.e. Rie L” sample containing 2.1973 ⁇ g (microgram) Fe.
  • FIG. 10 shows the actual Fe content, and the content as determined by the method and/or system of the present invention, using a spectrum analyzer (left: normal scale, right: enlarged scale) for Rienso® sample A (4500 ⁇ g Fe) to Rienso® sample L (2.1973 ⁇ g Fe).
  • FIG. 11 shows a frequency spectrum calculated using FFT for a signal measured using undersampling according to an embodiment of the present invention.
  • FIG. 12 shows a system for performing methods according to embodiments of the present invention.
  • FIG. 13 shows a typical heterodyne based receiver part, as can be used in embodiments of the present invention.
  • FIG. 14 illustrates a frequency spectrum corresponding with the heterodyne based receiver part of FIG. 13 , as can be used in embodiments of the present invention.
  • FIG. 15 illustrates a typical undersampling receiver part, as can be used in embodiments of the present invention.
  • FIG. 16 illustrates a frequency spectrum corresponding with the undersampling receiver part of FIG. 15 , as can be used in embodiments of the present invention.
  • FIG. 17 illustrates an example of a method for calibrating the system, as can be used in an embodiment of the present invention.
  • FIG. 18 illustrates an example of a phase shift calibration, as can be obtained using an embodiment of the present invention.
  • the particles presenting magnetic properties may for example be magnetic particles, magnetic nano-particles, target specific iron oxide particles and magnetic contrast agents, magnetic drug carriers particles for hyperthermia and thermo-ablation, pre-labeled cells, therapeutic cells and stem cells, and/or may be paramagnetic particles, super-paramagnetic iron oxide (SPIO) and ultra-small iron oxide particles (USPIO).
  • SPIO super-paramagnetic iron oxide
  • USPIO ultra-small iron oxide particles
  • first magnetic field reference is made to a magnetic field inducing orientation of the magnetization of the particles under study.
  • a magnetic field inducing orientation of the magnetization of the particles under study corresponds with the classic static magnetic field typically used for orienting magnetization of the particles under study in conventional EPR measurements.
  • the first magnetic field in the present example is not constant but is a time varying magnetic field.
  • RF excitation typically having for example a frequency in the order of between 1 MHz and 1 GHz, for example a frequency in the order between 60 MHz and 500 MHz.
  • nano-particles reference is made to particles having a critical dimension, e.g. diameter, in the range of 1 nm to 1000 nm.
  • the size of the particles is further specified to be in a range as provided.
  • the nano-particles or magnetic nano-particles may be single domain particles.
  • an object under study such an object may be a non-living object or a living object.
  • the object may be a body of a living creature, such as for example an animal or human body.
  • the object under study according to embodiments of the present invention are paramagnetic objects.
  • Embodiments of the present invention can also be used for in-vitro testing, e.g. for the quantification of cells linked with the magnetic objects.
  • Embodiments of the invention allow to quantify the magnetic objects with a high sensitivity and accuracy. Examples of applications include pure quantification to 3D imaging but are not limited thereto.
  • Objects under study may be paramagnetic objects as of nature or may be made at least partially magnetic by adding, e.g. through administering, magnetic particles, such as magnetic nanoparticles, to the object.
  • the administering step may be performed prior to application of the method according to embodiments of the present invention for detecting electron magnetic resonance of the object under study.
  • Method embodiments according to the present invention may thus encompass only the step of detecting upon interaction or the steps of generating the fields and detecting upon interaction.
  • EPR technique being a direct measurement technique that does not require further data analysis.
  • the EPR used in embodiments of the present invention, is a low field and low frequency EPR technique, where the perturbing electromagnetic field is applied in a continuous way (CW).
  • CW continuous way
  • the EPR technique used in embodiments of the present invention is a direct measurement not requiring further data analysis.
  • the present invention is related to determining a quantity (e.g. expressed in terms of mass, concentration or number of cells) of magnetic particles, such as for example paramagnetic particles, like e.g. paramagnetic nanoparticles, enclosed in a given volume.
  • the particles may be iron oxide nanoparticle, although embodiments are not limited thereto.
  • the method according to embodiments of the first aspect comprises applying a first magnetic field (B 0 ) to said volume for magnetizing said magnetic particles, the first magnetic field (B 0 ) being a time-varying field having a first magnitude and a first frequency (f B0 ). Simultaneously a second magnetic field (B 1 ), not parallel to the first magnetic field, is applied to said volume for causing precession of the magnetized particles, the second magnetic field being an RF field having a second frequency (f B1 ) chosen substantially equal to the Larmor-frequency (f L ) of electron spins of the magnetic particles when exposed to the first magnetic field (B 0 ).
  • the frequency of the second frequency (f B1 ) is equal to the Larmor frequency, some deviation could be present. Nevertheless, the larger the difference, the less sensitive the technique becomes.
  • the RF field B 1 varies in time with the Larmor frequency as indicated above.
  • the second magnetic field (B 1 ) is substantially orthogonal or orthogonal to the first magnetic field (B 0 ). Such orthogonal orientation can be obtained in an electronic and or mechanical way.
  • the first frequency used can be significantly lower than in conventional EPR systems.
  • the low frequency can for example be in the range 10 Hz to 30000 Hz for f B0 , and in the range 50 MHz to 1000 MHz for f B1 .
  • the frequency used for f B1 can for example be 300 MHz. It is an advantage of embodiments of the present invention that at these low frequencies, the attenuation inside tissues is less pronounced. The latter is advantageous if the technique is used with reference to in-vivo systems.
  • v 0 0. Nevertheless, v 0 may be different from 0 and may be a DC value, e.g. 100 mV.
  • the precession referred to is the precession of the magnetic moment with respect to the external magnetic field B 0 (electron spin).
  • the resultant magnetization (M) originating from the volume is measured whereby the resultant magnetization (M) is being modulated, for example amplitude modulated, by the time-varying field, B 0 .
  • the magnetization vector is the sum of all magnetic moments. The magnitude of the magnetization is correlated with the concentration of magnetic particles.
  • a discrete Fourier transform is performed on the voltage induced in the sensing element, representative for the magnetization.
  • the induced voltage is given by:
  • p R (r) denotes the receive coil sensitivity, which contains all geometrical parameters of the sensing element, for example the sensing element may be a coil.
  • the power and or voltage is calculated and a quantity of the magnetic particles enclosed in the volume is determined based on the power.
  • the signal obtained by a sensing element, is measured and discrete Fourier transform is applied. If the system is ideal and if there is no particle present, the signal is an unmodulated signal. If there is a particle present, the signal is a modulated signal. The modulated signal contains information of the magnetic particle. If a high speed ADC system is used with a sampling frequency, f s , chosen so the Nyquist-Shannon sampling theorem is fulfilled, information can be extracted direct by performing a discrete Fourier transform. The outcome of the DFT results in a set of frequencies and a frequency component is used for determining information regarding to the quantity of the iron being present.
  • a demodulation technique can be used where an envelope signal will be extracted and the DFT on the envelope signal will be performed.
  • the outcome of the DFT results in a set of frequencies and a frequency component is used for determining information regarding to the quantity of the iron being present. If the system is ideal one measures a sample without particles, the envelope is a DC value, if one measures a sample with particles, the envelope is the result of the Langevin and EPR contribution.
  • the envelope signal contains information of the magnetic particle. Determining the envelope signal can be performed in a plurality of ways, for example using a product detector or envelope demodulator circuit or using digital signal processing techniques. Alternatively, when undersampling is performed, the envelope is the direct result of the measurements performed.
  • the RF field B 1 can be modulated in amplitude and/or in frequency. Since the amplitude of B 0 can vary, also the Larmor frequency can vary. Depending on this variation, the frequency of B 1 can vary, e.g. a variation between a few Hz to 300 MHz could be implemented. In some embodiments such a variation may for example be f 0 ⁇ f with ⁇ f being equal to the bandwidth of the system.
  • the strength of the second magnetic field B 1 may be chosen according to the following procedure: The power of the B 1 signal is increased and simultaneously the amplitude of the spectral component is measured.
  • the spectral component may be f B1 +f B0 or f IF +f B0 in case of heterodyne based systems or f B0 in case of an undersampling receiver.
  • the optimal value for the strength of B 1 is the value where the power of the spectral component is maximal. Care is taken that the system is still operated as a linearly time invariant system.
  • the magnetic particle quantity is measured in a direct way and that not the endogenous particles, e.g. endogenous iron, i.e. those originating from within an organism, present in the biological tissue and fluid is measured. It thus is an advantage of embodiments that no additional measurements are required to extract endogenous particles.
  • endogenous particles e.g. endogenous iron, i.e. those originating from within an organism
  • EPR can be done at a single temperature (i.e. there is no need to measure at different temperatures).
  • the EPR measurement in embodiments of the present invention can be performed for example at room temperature or for example at about 37° C., i.e. a temperature close to the temperature of an animal or human body. Although not required a study of the particle effect as function of temperature still is possible.
  • the present invention is applicable for magnetic particles such as for example paramagnetic particles, including magnetic nano-particles, target specific iron oxide particles and magnetic contrast agents, magnetic drug carriers particles for hyperthermia and thermo-ablation, pre-labeled cells, therapeutic cells and stem cells, and/or may be paramagnetic particles, super-paramagnetic iron oxide (SPIO) and ultra-small iron oxide particles (USPIO).
  • paramagnetic particles including magnetic nano-particles, target specific iron oxide particles and magnetic contrast agents, magnetic drug carriers particles for hyperthermia and thermo-ablation, pre-labeled cells, therapeutic cells and stem cells, and/or may be paramagnetic particles, super-paramagnetic iron oxide (SPIO) and ultra-small iron oxide particles (USPIO).
  • SPIO super-paramagnetic iron oxide
  • USPIO ultra-small iron oxide particles
  • the EPR technique used does not make use of a cavity. This is an advantage to use the technique and system related to in-vivo systems.
  • the principle of the measurement proposed by the present invention is based on the non-linear behavior of the magnetic particle and/or paramagnetic particle in an applied magnetic field B 0 , described by the Langevin theory and the electro-paramagnetic resonance response to a magnetic RF-field.
  • a magnetic particle and/or paramagnetic particle is placed in a static magnetic field B 0 , it will align according to this field B 0 . If the particle is then additionally excited by an RF-field B 1 (t), oriented orthogonal to the static field B 0 , and having a frequency f B1 (chosen equal or almost equal to the Larmor frequency f L of the particle of interest, e.g. Fe, in said static field B 0 ), a precession of the magnetic vector M of the iron particles about the axis of the magnetic field B 0 will occur. This phenomenon per se is known in the art, and is illustrated in FIG.
  • the black vector M represents the magnetization vector M of the magnetic particle, paramagnetic particle, which vector rotates around the Z-axis at an angular velocity ⁇ L , characteristic for each atom.
  • the power applied to the T x -coil is maximal so that the angle ⁇ becomes 90°.
  • y(t) cos(2 ⁇ f B 1 t) is the modulation term, e.g. amplitude modulation term.
  • Equation [2] is an amplitude modulated signal in the time-domain, which has a frequency spectrum as shown in FIG. 6 .
  • FIG. 1 shows a flow-chart of an embodiment of a method according to the present invention
  • FIG. 2 shows a schematic block-diagram of a system according to an embodiment of the present invention.
  • a volume 2 comprising an unknown amount of a particular paramagnetic particle (e.g. iron oxide) is provided, and that the amount of iron in the volume is to be determined.
  • the amount or quantity can be expressed as the mass, concentration, number of cells, or in other suitable ways).
  • the first magnetic field thus is a time varying magnetic field.
  • the frequency f B0 can be in a range from several Hz to over the 100 kHz. Higher frequencies have an advantage because noise is in receivers mainly dominated by 1/f behavior, however this frequency may not become too high because particles has finite relaxation times, i.e. particles can only follow a variation up to a specific frequency.
  • SAR specific absorption rate
  • the SAR is proportional to the square of the field amplitude and frequency.
  • a second magnetic field B 1 (t), oriented orthogonal to the field B 0 , and having a frequency f B1 substantially equal to the Larmor frequency of the particle of interest (in the example: iron) is simultaneously applied to the volume 2.
  • the frequency f B1 f L may be for example 300 MHz.
  • the field strength may be much lower up to 7 mT in case of 300 MHz excitation. Due to the applied first and second magnetic field B 0 and B 1 , the magnetic particle, e.g.
  • paramagnetic particles will show a magnetization M which is a combination of two effects: the first effect can be described by Langevin equations, the second effect can be described by EPR absorption. This is illustrated in FIG. 3 .
  • the measured signal shows in a direct way the combination of the EPR and Langevin contributions.
  • the technique and system also allows to measure hysteresis effects of the particles. The technique and system thus allows to extract a lot of information about the particle behavior.
  • this magnetization signal M(t) is measured using a sensing element.
  • the measured signal is modulated due to the time variable first magnetic field that is used.
  • the at least one frequency component may be determined for example by means of a spectrum analyzer or by other means capable of performing a (Discrete) Fourier-Transform such as for example a computer program or a suitably programmed Digital Signal Processor (DSP) or Field Programmable Gate Array (FPGA).
  • DSP Digital Signal Processor
  • FPGA Field Programmable Gate Array
  • the obtained result may for example be evaluated based on theoretically expected results, by comparing with a calibration method, using look up tables, using an algorithm, . . . .
  • the power of at least one frequency component e.g. the peaks at the P 1_USB and/or the P 1_LSB of a known sample, e.g. of a Rienso® A sample (further abbreviated as Rie A with 4500 ⁇ g Fe) may be used as a reference value.
  • the amount (e.g. quantity or mass or concentration) of magnetic particles, e.g. paramagnetic particles, present in an unknown specimen can be determined, as will become clear by the following experimental results.
  • the method comprises a calibration phase.
  • a start-up sequence can be performed including a calibration step, resulting in an optimum detection limit.
  • FIG. 17 An example of such a sequence is shown in FIG. 17 , illustrating a power-up of the system, an initialization of the system, and after a system warm-up, a calibration phase thereafter resulting in a system ready for measurement.
  • phase shift can be performed in a digital manner, an analog manner or a combination.
  • the goal is to set an optimal point (OP) in such a way that received power or voltage at P 1_USB (or P 1_LSB ) is minimized, i.e. as close as possible to the noise floor of the system.
  • An example of the phase optimization is shown in FIG. 18 .
  • This calibration step improves the sensitivity of the system (i.e. detection limit) and the accuracy and precision of the final result.
  • This calibration step is especially relevant in a non-orthogonal coil system, i.e.
  • T x -, R x -coil and the Helmholtz coil are not electrical orthogonal. It is to be noted that the optimal point is sensitive to (thermal) drift, to obtain the most accurate results thermal drift needs to be minimized and the calibration step needs to be repeated on a regular basis. Once the calibration is performed the system is ready for measurements.
  • the present invention also relates to a system for determining a quantity of magnetic particle, e.g. paramagnetic particles, in an object.
  • a system for determining a quantity of magnetic particle, e.g. paramagnetic particles, in an object.
  • the system comprises a first signal source and a first magnetic field inducing element, e.g. a coil, for generating and applying a first magnetic field (B 0 ) to said volume for magnetizing said magnetic particles, e.g. paramagnetic particles, the first magnetic field (B 0 ) being a time-varying field having a first magnitude and a first frequency (f B0 ).
  • the system also comprises a second signal source and a second magnetic field inducing element, e.g. coil, arranged for simultaneously applying to said volume a second magnetic field (B 1 ) orthogonal to the first magnetic field (B 0 ), and having a frequency f B1 equal to the Larmor frequency (f L ) of said magnetic particles, e.g. paramagnetic particles, for causing precession of the magnetized particles.
  • the system also comprises a measurement unit, e.g. a coil, for measuring the resultant magnetization, the resultant magnetization (M) being modulated by the time varying field, e.g. amplitude modulated.
  • the measurement unit may be any suitable sensor allowing measurement of magnetization.
  • FIG. 11 shows a frequency spectrum calculated using a Fast Fourier Transform.
  • the software tool Matlab 2012b were used.
  • the signal was measured using an undersampling or bandpass sampling approach whereby an ADC sampling at a rate 75 MSPS was used.
  • a on the shelf solution for the DAC/ADC FMC card (FMC176) and a high-performance with advanced Digital Signal Processing and multiple I/O options (PC720) where used.
  • the specific cables used give rise to specific losses, resulting in possible small differences for different measurements, as can be seen in the experiment shown in FIG. 11 and the experiment described by table 2.
  • FIG. 12 shows the system used for measuring the frequency spectrum shown in FIG. 11 .
  • the time required for taking measurements depends on the particle concentration, whereby lower concentrations require a longer measurement time. In the experiments performed, a typical experiment measurement time was 25 to 60 seconds.
  • the exemplary system shown in FIG. 12 illustrates some standard and optional components of a system according to an embodiment of the present invention.
  • the system comprises a magnetic field B 0 generation part 1210 .
  • a magnetic field B 0 generation part 1210 .
  • Such part may comprise a waveform generator and a magnetic field B 0 source.
  • the waveform generator may be provided with a common clock signal as a reference signal.
  • the waveform generator can be a separate block or it can be part of the B 0 source.
  • the system also comprises a coil part 1220 , wherein a Helmholtz type coil is fed with a magnetic field signal from the B 0 generation part, a transmit coil is provided and a sensing element is provided.
  • the sample holder and a sample are positioned therein.
  • the coil part typically may be a shielded enclosure and may be configured to be a temperature controlled environment.
  • the system also comprises an RF part 1230 , wherein a transmission part for feeding the transmit coil and a receiver part for feeding the sensing element, is provided.
  • the system furthermore comprises a signal processing part 1240 configured for signal generation, data acquisition and digital signal processing.
  • the signal processing part 1240 typically may be fed with the same reference clock as the waveform generator.
  • the signal processing part 1240 also may comprise a triggering element for linking the waveform generator signal with the obtained results.
  • the signal processing part 1240 typically also comprises one or more analogue to digital convertors and/or digital to analogue converters.
  • an FPGA and/or digital signal processing block a memory block with a FIFO-RAM and possible firmware.
  • the signal processing part 1240 may comprise a power sensor for measuring the power for controlling and/or sweeping the applied power to the transmit coil.
  • a bus e.g. a high speed bus may be used for providing communication with a computing system.
  • a computing system may provide conventional components such as a motherboard, a processor, a memory such as a random access memory.
  • a solid state device memory or hard disk memory also may be provided.
  • Other components such as an input device, like a keyboard, an output device, like a screen, and a video card also may be present.
  • the receiver part may be a heterodyne receiver part.
  • the spectral components are down-converted around f IF .
  • the IF signal is digitized using a ADC (analog-to-digital converter).
  • the ADC sampling frequency, f s is chosen so the Nyquist-Shannon sampling theorem is fulfilled, i.e. min. twice the upper cut-off frequency.
  • An example of a heterodyne receiver is shown in FIG. 13 and a corresponding frequency spectrum is shown in FIG. 14 .
  • the receiver part may be an undersampling system.
  • the B 1 signal is digitized at a sample rate below the Nyquist rate.
  • f B1 ⁇ nf B0 is down-converted to DC and the spectral components ⁇ nf B0 around f B1 are after down-conversion lying around the DC value.
  • a narrow bandwidth band pass filter is used so that the harmonics of B1 are sufficient suppressed before applying the signal to the ADC.
  • An example of an undersampling based receiver is shown in FIG. 15 and a corresponding frequency spectrum is shown in FIG. 16 .
  • FIG. 19 shows the measured quantity of iron using an undersampling based receiver.
  • Embodiments of present invention may comprise magnetic field gradient generators adapted for imaging and/or volumetric imaging purposes. Such embodiments may furthermore comprise a procession unit adapted for combining the detected signals in the form of image and/or volumetric image representations of the object under test.
  • imaging could be performed by inducing a field gradient over the sample.
  • a field gradient e.g. 0 ⁇ 10 mT
  • the spins will give a different response depending on their position (corresponding with the Langevin equation).
  • Applying different field gradients e.g. 0 ⁇ 5 mT, 10 ⁇ 0 mT, . . . , 0 ⁇ 10 mT, ⁇ 10 ⁇ 0 mT, 0 ⁇ 5 mT
  • resonance condition is created only at one position, ⁇ 10 mT at one location and 0 mT at all the other locations.
  • FIG. 5 describes an experimental setup as proof of the concept.
  • the R x -coil can be oriented in any suitable orientation. Maximum sensitivity is obtained when the R x -coil is oriented perpendicularly to the T x -coil.
  • this signal is applied to a RF T x -coil in a shielded & thermal controlled excitation chamber 75 .
  • This chamber also contains a Helmholtz type coil for generating a time-varying magnetic field B 0 (t).
  • This voltage controlled oscillator uses the stable voltage and the reference oscillator signal generated in the first chamber 71 .
  • the magnetic field B 1 (t) generated by the RF T x -coil and the magnetic field B 0 (t) generated by the Helmholtz type coil are oriented orthogonal to each other.
  • a third coil, referred to as RF R x -coil is also present in the shielded & thermal controlled excitation chamber 73 , for measuring the resultant magnetization signal originating from the volume containing the sample to be measured.
  • the output of this RF R x -coil is applied to a low noise amplification and filtering stage 75 and to a signal analyzer 76 .
  • a spectrum analyzer which has typically a heterodyne receiver
  • the sample is placed inside the T x - and R x -coil which are both placed together with the sample inside the Helmholtz type of coil all placed in the shielded & thermal controlled excitation chamber 73 .
  • FIG. 6 shows the signal as can be seen on the signal analyzer 76 , showing a number of peaks (also called side-bands) centered around 300 MHz at distances which are multiples of 200 Hz. The highest peak is representative of the Larmor frequency being applied to the volume by means of the first coil, while the other peaks are caused by the interaction with the paramagnetic nano-particle of the specimen under test.
  • FIG. 7 shows the same spectrum as FIG. 6 , but zoomed in at a frequency band from about (300 MHz ⁇ 100 Hz) to about (300 MHz+500 Hz).
  • each dilution sample was measured three times (indicated under heading Measured I, II, III).
  • the power of the first upper sideband (spectral component P 1_USB ) was measured (in dBm), and then converted to a voltage value.
  • the mass of the other samples is measured & calculated in the same manner. (It is noted that the above calculations are not optimized for accuracy, but only to demonstrate the feasibility of the method).
  • FIG. 10 gives a graphical representation of the actual Fe content and the measured Fe content by using embodiments of the present invention for Rie samples A to L. As can be seen, the results are quite accurate, over a relatively large range (from 4500 ⁇ g to 2.19 ⁇ g), which is more than three orders of magnitude.
  • embodiments of the present invention also relate to computer-implemented methods for performing at least part of the methods as indicated above.
  • the methods may be implemented in a computing system. They may be implemented as software, as hardware or as a combination thereof. Such methods may be adapted for being performed on computer in an automated and/or automatic way. In case of implementation or partly implementation as software, such software may be adapted to run on suitable computer or computer platform, based on one or more processors.
  • the software may be adapted for use with any suitable operating system such as for example a Windows, Linux or any other operating system.
  • the computing means may comprise a processing means or processor for processing data.
  • the processing means or processor may be adapted for determining a quantity of magnetic particles, e.g. paramagnetic particles, enclosed in a volume according to any of the methods as described above.
  • the computing system furthermore may comprise a memory system including for example ROM or RAM, an output system such as for example a CD-rom or DVD drive or means for outputting information over a network.
  • Conventional computer components such as for example a keyboard, display, pointing device, input and output ports, etc also may be included.
  • Data transport may be provided based on data busses.
  • the memory of the computing system may comprise a set of instructions, which, when implemented on the computing system, result in implementation of part or all of the standard steps of the methods as set out above and optionally of the optional steps as set out above.
  • the obtained results may be outputted through an output means such as for example a plotter, printer, display or as output data in electronic format.
  • inventions of the present invention encompass computer program products embodied in a carrier medium carrying machine readable code for execution on a computing device, the computer program products as such as well as the data carrier such as dvd or cd-rom or memory device. Aspects of embodiments furthermore encompass the transmitting of a computer program product over a network, such as for example a local network or a wide area network, as well as the transmission signals corresponding therewith.

Landscapes

  • Physics & Mathematics (AREA)
  • General Physics & Mathematics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Optics & Photonics (AREA)
  • Investigating Or Analyzing Materials By The Use Of Magnetic Means (AREA)
US15/549,466 2015-02-09 2016-02-08 System and method for determining a quantity of magnetic particles Active 2036-03-06 US10605751B2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP15154399 2015-02-09
EP15154399 2015-02-09
EP15154399.8 2015-02-09
PCT/EP2016/052625 WO2016128353A1 (en) 2015-02-09 2016-02-08 System and method for determining a quantity of magnetic particles

Publications (2)

Publication Number Publication Date
US20180031500A1 US20180031500A1 (en) 2018-02-01
US10605751B2 true US10605751B2 (en) 2020-03-31

Family

ID=52462222

Family Applications (1)

Application Number Title Priority Date Filing Date
US15/549,466 Active 2036-03-06 US10605751B2 (en) 2015-02-09 2016-02-08 System and method for determining a quantity of magnetic particles

Country Status (6)

Country Link
US (1) US10605751B2 (de)
EP (1) EP3256842B1 (de)
JP (1) JP6757324B2 (de)
KR (1) KR102212619B1 (de)
RU (1) RU2727551C2 (de)
WO (1) WO2016128353A1 (de)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017190307A1 (zh) * 2016-05-05 2017-11-09 中国科学技术大学 一种磁共振谱仪及基于fpga的磁共振谱仪控制装置
CN109541014B (zh) * 2018-12-26 2022-09-06 河南工业大学 一种基于磁信号的磁性纳米粒子质量检测方法
CN109839610B (zh) * 2018-12-27 2021-02-12 中国计量科学研究院 基于正交原理的亥姆霍兹线圈常数交流校准***及方法
CN110414116B (zh) * 2019-07-23 2021-05-04 中山大学 一种颗粒材料的颗粒状态分析方法、装置及设备
CN117929217A (zh) * 2024-03-22 2024-04-26 宁德时代新能源科技股份有限公司 磁性颗粒含量的检测***以及检测方法

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2859403A (en) 1956-09-14 1958-11-04 Schlumberger Well Surv Corp Magnetic resonance apparatus
US20010028247A1 (en) 1994-08-26 2001-10-11 King James D. Porosity and permeability measurement of underground formations containing crude oil, using EPR response data
US20030232084A1 (en) * 1999-04-09 2003-12-18 Groman Ernest V. Polyol and polyether iron oxide complexes as pharmacological and/or MRI contrast agents
US20050053250A1 (en) * 2003-09-10 2005-03-10 Jacobus Jonkman Directional hearing aid tester
US20050237058A1 (en) 2004-04-15 2005-10-27 Jeol Ltd. Method of quantifying magnetic resonance spectrum
US20070155024A1 (en) * 2003-02-28 2007-07-05 Peter Miethe Method and device for selectively detecting ferromagnetic or superparamagnetic particles.
RU2415433C2 (ru) 2005-01-31 2011-03-27 Конинклейке Филипс Электроникс Н.В. Быстрое и чувствительное измерение биоинформации
JP2012504247A (ja) 2008-09-30 2012-02-16 アイメック パルスｅｐｒ検出
US20120126800A1 (en) * 2009-08-07 2012-05-24 Koninklijke Philips Electronics N.V. Apparatus and method for determining at least one electromagnetic quantity
US20140009159A1 (en) 2011-03-22 2014-01-09 Pepric Nv Isolating active electron spin signals in epr
US20150268369A1 (en) * 2012-10-12 2015-09-24 Geotech Airborne Limited Calibrated electromagnetic survey system

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2859403A (en) 1956-09-14 1958-11-04 Schlumberger Well Surv Corp Magnetic resonance apparatus
US20010028247A1 (en) 1994-08-26 2001-10-11 King James D. Porosity and permeability measurement of underground formations containing crude oil, using EPR response data
US20030232084A1 (en) * 1999-04-09 2003-12-18 Groman Ernest V. Polyol and polyether iron oxide complexes as pharmacological and/or MRI contrast agents
US20070155024A1 (en) * 2003-02-28 2007-07-05 Peter Miethe Method and device for selectively detecting ferromagnetic or superparamagnetic particles.
US20050053250A1 (en) * 2003-09-10 2005-03-10 Jacobus Jonkman Directional hearing aid tester
US20050237058A1 (en) 2004-04-15 2005-10-27 Jeol Ltd. Method of quantifying magnetic resonance spectrum
JP2005326397A (ja) 2004-04-15 2005-11-24 Jeol Ltd 磁気共鳴スペクトルの定量方法
US7106059B2 (en) 2004-04-15 2006-09-12 Jeol Ltd. Method of quantifying magnetic resonance spectrum
RU2415433C2 (ru) 2005-01-31 2011-03-27 Конинклейке Филипс Электроникс Н.В. Быстрое и чувствительное измерение биоинформации
JP2012504247A (ja) 2008-09-30 2012-02-16 アイメック パルスｅｐｒ検出
US20120049847A1 (en) 2008-09-30 2012-03-01 Imec Pulsed epr detection
US8816685B2 (en) 2008-09-30 2014-08-26 Imec Pulsed EPR detection
US20120126800A1 (en) * 2009-08-07 2012-05-24 Koninklijke Philips Electronics N.V. Apparatus and method for determining at least one electromagnetic quantity
US20140009159A1 (en) 2011-03-22 2014-01-09 Pepric Nv Isolating active electron spin signals in epr
JP2014508947A (ja) 2011-03-22 2014-04-10 ペプリク・ナムローゼ・フェンノートシャップ 電子常磁性共鳴におけるアクティブな複数の電子スピン信号の分離
US9551773B2 (en) 2011-03-22 2017-01-24 Pepric Nv Isolating active electron spin signals in EPR
US20150268369A1 (en) * 2012-10-12 2015-09-24 Geotech Airborne Limited Calibrated electromagnetic survey system

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
Anderson, "Applications of Modulation Techniques to High Resolution Nuclear Magnetic Resonance Spectrometers", The Review of Scientific Instruments vol. 33, No. 11, Nov. 1962, pp. 1160-1166.
Chevion et al., "High Resolution EPR Studies of the Fine Structure of Heme Proteins. Third Harmonic Detection Approach", Biochimica et Biophysica Acta vol. 490, No. 2, Feb. 22, 1977, pp. 272-278.
Coene et al., "Quantitative Estimation of Magnetic Nanoparticle Distributions in One Dimension Using Low-Frequency Continuous Wave Electron Paramagnetic Resonance", Journal of Physics D: Applied Physics vol. 46, No. 24, Jun. 19, 2013, pp. 1-10.
European Search Report From EP Application No. 15154399.8, dated Apr. 20, 2015.
Fedin et al., "Absorption Line CW EPR Using an Amplitude Modulated Longitudinal Field", Journal of Magnetic Resonance vol. 171, 2004, pp. 80-89.
Gamarra et al., "Ferromagnetic Resonance for the Quantification of Superparamagnetic Iron Oxide Nanoparticles in Biological Materials", International Journal of Nanomedicine vol. 5, Mar. 24, 2010, pp. 203-211.
Gleich et al., "Tomographic Imaging Using the Nonlinear Response of Magnetic Particles", Nature vol. 435, Jun. 30, 2005, pp. 1214-1217.
Haworth et al., "The Use of Modulation in Magnetic Resonance", Progress in Nuclear Magnetic Resonance Spectroscopy vol. 1, Jan. 1, 1966, pp. 1-14.
International Search Report From PCT Application No. PCT/EP2016/052625, dated May 18, 2016.
Japanese Office Action from corresponding JP Application No. 2017-541838, dated Dec. 3, 2019.
Russian Office Action from RU Application No. 2017131335/28(054806), dated Jun. 4, 2019.

Also Published As

Publication number Publication date
JP6757324B2 (ja) 2020-09-16
RU2727551C2 (ru) 2020-07-22
KR102212619B1 (ko) 2021-02-05
RU2017131335A3 (de) 2019-06-04
RU2017131335A (ru) 2019-03-11
JP2018508016A (ja) 2018-03-22
KR20170115548A (ko) 2017-10-17
WO2016128353A1 (en) 2016-08-18
EP3256842A1 (de) 2017-12-20
US20180031500A1 (en) 2018-02-01
EP3256842B1 (de) 2021-07-07

Similar Documents

Publication Publication Date Title
US10605751B2 (en) System and method for determining a quantity of magnetic particles
Liu et al. Calculation of susceptibility through multiple orientation sampling (COSMOS): a method for conditioning the inverse problem from measured magnetic field map to susceptibility source image in MRI
US6477398B1 (en) Resonant magnetic susceptibility imaging (ReMSI)
Klomp et al. Amide proton transfer imaging of the human breast at 7T: development and reproducibility
US9383423B2 (en) Systems and methods for susceptibility tensor imaging
US9943246B2 (en) System and method for assessing susceptibility of tissue using magnetic resonance imaging
JPH0222348B2 (de)
WO1998053336A1 (en) Magnetic resonance method and apparatus for determining or imaging longitudinal spin relaxation time or producing images which substantially reflect longitudinal spin relaxation time contrast
JP5666470B2 (ja) 核磁気共鳴イメージング装置およびそのｓａｒの見積方法
TOP An arbitrary waveform magnetic nanoparticle relaxometer with an asymmetricalthree-section gradiometric receive coil
US20140103929A1 (en) Systems and methods for susceptibility tensor imaging in the p-space
Deng et al. Fast EPR imaging at 300 MHz using spinning magnetic field gradients
Belkic Molecular imaging through magnetic resonance for clinical oncology
Zampetoulas et al. Correction of environmental magnetic fields for the acquisition of Nuclear magnetic relaxation dispersion profiles below Earth’s field
EP2378281A1 (de) Verfahren zum Messen Elektronenrelaxation bei T1-EPR-Tomographie und System zur Anwendung des Verfahrens
JP5267978B2 (ja) 核磁気共鳴イメージング装置
Dabek et al. SQUID-sensor-based ultra-low-field MRI calibration with phantom images: Towards quantitative imaging
Awojoyogbe et al. Theory, dynamics and applications of magnetic resonance imaging-I
Yamashita et al. Thermal noise calculation method for precise estimation of the signal-to-noise ratio of ultra-low-field MRI with an atomic magnetometer
Giovannetti et al. Simulation and comparison of coils for Hyperpolarized 13C MRS cardiac metabolism studies in pigs
Fiorito et al. Fast, interleaved, Look‐Locker–based T 1 mapping with a variable averaging approach: Towards temperature mapping at low magnetic field
JP5392803B2 (ja) 核磁気共鳴イメージング装置
Scotti et al. Phase‐independent thermometry by Z‐spectrum MR imaging
PL241624B1 (pl) Układ do lokalizacji zmian nowotworowych i miażdżycowych metodą obrazowania EPRI
Maehara et al. Optimization of Look-Locker Turbo-Field Echo-Planar Imaging and Evaluation of Its Accuracy in Head and Neck 3D T1 Mapping

Legal Events

Date Code Title Description
AS Assignment

Owner name: PEPRIC NV, BELGIUM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:VERBIEST, JOERI;REEL/FRAME:043229/0018

Effective date: 20170801

FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO SMALL (ORIGINAL EVENT CODE: SMAL); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: NOTICE OF ALLOWANCE MAILED -- APPLICATION RECEIVED IN OFFICE OF PUBLICATIONS

STPP Information on status: patent application and granting procedure in general

Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED

STPP Information on status: patent application and granting procedure in general

Free format text: AWAITING TC RESP, ISSUE FEE PAYMENT VERIFIED

STPP Information on status: patent application and granting procedure in general

Free format text: PUBLICATIONS -- ISSUE FEE PAYMENT VERIFIED

STCF Information on status: patent grant

Free format text: PATENTED CASE

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

FEPP Fee payment procedure

Free format text: SURCHARGE FOR LATE PAYMENT, SMALL ENTITY (ORIGINAL EVENT CODE: M2554); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2551); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

Year of fee payment: 4